[X-chromosome dominant chondrodysplasia punctata (Happle) in a boy]. / X-chromosomal dominante Chondrodysplasia punctata (Happle) bei einem Knaben.

The case of a newborn boy with ichthyosiform erythroderma, asymmetrical shortening of the femur and sectorial cataract is reported. The hyperkeratotic areas cleared within 2 months, resulting in follicular atrophoderma. The clinical findings and course of the disease, and also the histological and ultrastructural features, indicate an X-linked dominant chondrodysplasia punctata (Happle). Since a normal male karyotype (46, XY) is present, a half-chromatid mutation of the maternal gamete and a somatic mutation are considered as possible explanations for this mosaic phenotype.

Encephalocele, radial defects, cardiac, gastrointestinal, anal, and renal anomalies: a new multiple congenital anomaly (MCA) syndrome?

We present two unrelated female patients with a complex pattern of congenital malformations including encephalocele, oesophageal atresia, abnormal lung lobation, congenital heart defects, anal anomalies, liver, spleen and radial defects. Clinical variability between the two cases can be seen as a result of variable expression. The pattern of anomalies in these two unrelated patients suggest that they may represent the same, as yet unknown, syndrome.

[Diagnosis of fetal virus infections by in situ hybridization]. / Die Diagnostik fetaler Virusinfektionen durch In-situ-Hybridisierung.

Non-radioactive in situ hybridization of formalin-fixed paraffin-embedded placental and foetal tissue, using virus-specific DNA or RNA probes, may be helpful for the diagnosis of foetal virus infection causing foetal hydrops, granulomatous placentitis and abortion. We present four cases of intrauterine CMV-, Parvo-B19- and Varicella-Zoster virus infection, in which this diagnostic method established detection of the virus.

Molecular heterogeneity of the fragile X syndrome.

The fragile X syndrome is an X-linked disorder which has been shown to be associated with the length variation of a DNA fragment containing a CGG trinucleotide repeat element at or close to the fragile site. Phenotypically normal carriers of the disorder generally have a smaller length variation than affected individuals. We have cloned the region in cosmids and defined the area containing the amplified sequence. We have used probes from the region to analyse the mutation in families. We show that the mutation evolves in different ways in different individuals of the same family. In addition we show that not all fragile X positive individuals show this amplification of DNA sequence even though they show expression of the fragile site at levels greater than 25%. One patient has alterations in the region adjacent to the CGG repeat elements. Three patients in fragile X families have the normal fragment with amplification in a small population of their cells. These observations indicate that there is molecular heterogeneity in the fragile X syndrome and that the DNA fragment length variation is not the only sequence responsible for the expression of the fragile site or the disease phenotype.

Early prenatal diagnosis of the fragile site at Xq27.3 associated with Martin-Bell syndrome.

Early prenatal diagnosis of the fragile X was attempted in 44 pregnancies, including one twin pregnancy at risk of Martin-Bell (MB) syndrome. The sex ratio was 24M:21F. The fragile site was reproducibly demonstrated in cultured chorionic villus (CV) cells in eight male and five female fetuses. Six of the male and three of the female fetuses were terminated. Simultaneous RFLP analysis provided confirmative data with flanking DNA markers in 3 of 13 analysed cases. Recombination and/or non-informativeness at available distal and/or proximal loci were found in nine cases. In one male fetus, discordance between the haplotype and cytogenetics (fragile-X-negative) suggested the presence of a normal male transmitter, a double meiotic cross-over within the region, or a false-negative cytogenetic diagnosis. However, discordance between prenatal and post-termination/postnatal cytogenetic findings was not observed in this series. The use of excess thymidine for induction of the fragile X in cultured CV cells provided in the majority of cases a safe and rapid method for cytogenetic diagnosis, with options for early induced termination in fragile-X-positive pregnancies, for simultaneous RFLP analysis, and for subsequent second-trimester analysis of fetal blood in complicated cases.

[Neurofibromatosis--new clinical and molecular genetic aspects]. / Neurofibromatose--neue klinische und molekulargenetische Aspekte.

Neurofibromatosis is not a single entity. Seven types of the disorder are now known, which can be differentiated by clinical and genetic features. The wide variety of clinical manifestations makes close interdisciplinary cooperation necessary, in which the dermatologist frequently has a key role. The most frequent forms are peripheral neurofibromatosis (NF1) and central neurofibromatosis (NF2), for which separate gene localizations have been found on chromosomes 17 and 22, respectively, by molecular genetics techniques. The meanwhile possible prenatal diagnosis raises ethical questions.

Physical mapping across the fragile X: hypermethylation and clinical expression of the fragile X syndrome.

The most common genetic cause of mental retardation after Down's syndrome, the fragile X syndrome, is associated with the occurrence of a fragile site at Xq27.3. This X-linked disease is intriguing because transmission can occur through phenotypically normal males. Theories to explain this unusual phenomenon include genomic rearrangements and methylation changes associated with a local block of reactivation of the X chromosome. Using microdissected markers close to the fragile site, we have been able to test these hypotheses. We present evidence for the association of methylation with the expression of the disease. However, there is no simple relationship between the degree of methylation and either the level of expression of the fragile site or the severity of the clinical phenotype.

Mental retardation, acromegalic face, and megalotestes in two half-brothers: a specific form of X-linked mental retardation without fra(X) (q)?

We describe a family with two half-brothers affected with severe mental retardation. The phenotype in the affected individuals is characterized by apparent acromegaly, profound mental retardation, and hyperactivity. The mother has analogous but less severe facial anomalies and mild mental impairment. Screening for fra(X) (q) was negative in peripheral lymphocytes using methotrexate for fra(X) enhancement. The clinical findings in our patients are similar to those described by Fryns et al. [1986] in two patients with acquired lesions of the central nervous system. CT investigations in one of our patients showed areas of hyperdensity in the pontine region and a small subarachnoid cyst. The pedigree suggests X-linked inheritance. The association of apparent acromegaly, CNS anomalies, megalotestes, and mental retardation in this family supports the hypothesis that a distinct syndrome may exist with phenotype anomalies more severe than those characteristic for the Martin-Bell syndrome but without fragile X.

Guidelines for the preparation and analysis of the fragile X chromosome in lymphocytes.

The following guidelines were adopted by an Ad Hoc Committee convened at the Fourth International Workshop on the Fragile X Syndrome and X-Linked Mental Retardation to establish minimum cytogenetic standards for the preparation and analysis of the fragile X chromosome. The intention of the committee was to develop and provide practical standards for the routine cytogenetic detection of the fragile X. The guidelines describe reasonable criteria for effective tissue culture methods for eliciting the Xq27.3 fragile site in vitro and for the analysis of such chromosome preparations.

Relationship between age and IQ among fragile X males: a multicenter study.

Longitudinal decline in IQ among fragile X males was reported recently. However, there are problems in retesting IQ that may affect scores. Two such factors are intertest time interval and score obtained on the first test. To determine the generality of IQ score changes, we examined 101 fragile X males from 6 centers. To ensure high test-retest reliability, only results from Stanford-Binet and Wechsler tests were used. Thus there were retest scores from 60 subjects. Test-retest reliability between first and last scores was very good (r = 0.85) and comparable to those seen in nonfragile X mentally retarded individuals. Also computed were z-scores of differences in IQ scores. The z-score differences were distributed about a mean at 1 SD below the expected zero value. Eighteen subjects showed statistically significant decreases in IQ, 6 showed statistically significant increases, while 5 showed the same scores. Z-score differences were not correlated with type of residence or elapsed intertest interval, but were negatively correlated with first score obtained, indicating a regression-to-the-mean effect. Using a multiple regression analysis, we found first score obtained, age tested, and age retested significant predictors of score differences, accounting for 19% of the total variance. These results suggest that factors previously identified as affecting retest scores have a smaller effect than originally thought. It is suspected that decline in IQ is associated with dynamic neurological processes and needs to be investigated further.

Amelia: incidence and associated defects in a large population.

Amelia, or complete absence of a limb, is a very rare congenital anomaly. The incidence of amelia in a population of 1,213,913 consecutive livebirths in British Columbia during the period 1952-1984 was studied using the records of a population-based registry with multiple sources of ascertainment. There were 18 cases of amelia, giving a minimal incidence rate of 0.15 per 10,000 livebirths for this birth defect. Amelia occurred equally frequently in upper and lower limbs, and 11 of 18 (61%) liveborn cases also had malformations of other organ systems. In the group with lower limb amelia a specific pattern of associated malformations, which included omphalocele and diaphragmatic defects, was identified. There was no evidence for familial recurrence of amelia. Conditions to be considered in differential diagnosis are discussed.

An intronic region within the human factor VIII gene is duplicated within Xq28 and is homologous to the polymorphic locus DXS115 (767).

The genomic sequences recognized by the anonymous probe 767 (DXS115) are localized to two sites within Xq28. One site lies within intron 22 of the factor VIII gene (FBC). Physical mapping suggests that the second site lies within 1.2 megabases of the F8C gene. The RFLPs detected by 767 are located within the second site. Genetic data suggest that F8C and DXS115 are tightly linked (theta max = .04; Zmax = 8.30). Recombination events in meioses informative for DXS52 (St14), DXS115, and F8C suggest that DXS115 and F8C lie distal to DXS52.

[Knee pterygium syndrome in a newborn infant]. / Kniepterygium-Syndrom bei einem Neugeborenen.

We report on a newborn boy with popliteal pterygium syndrome. Congenital anomalies included popliteal pterygia, symblepharon, cleft lip and palate with syngnathia, severe hypoplasia of both thumbs, a characteristic nail anomaly of both first toes, multiple syndactylies, and a hypoplastic scrotum with cryptorchidism. Mental development can be expected to be normal. Overall prognosis of the disorder after detailed operative correction is apparently favorable. Differential diagnosis is discussed in detail. The syndrome is autosomal dominantly inherited, our patient represents an isolated case.

Clinico-neurological investigations in the fra(X) form of mental retardation.

A clinical, neurological and electroencephalographic investigation was undertaken in 29 previously cytogenetically verified hemizygous males with the fra(X) form of mental retardation (age range 3.5 to 59 years); in addition, 6 heterozygous females were examined. All male patients displayed the known physical aspects of this syndrome together with associated abnormalities of the palate, skeleton, connective tissue and endocrine system. The most prominent neurological features were different forms of oculomotor disturbances, minor motor and pyramidal signs, incoordination, muscle hypotonia, gait and speech abnormalities. There was no increased frequency either in seizures or in epileptic EEG discharges. Some patients had a slowing of background activity in EEG. About 50% of all patients displayed autistic-like behaviour, short attention span and/or hyperactivity. In accordance with the literature, the findings indicate that there are no neurological, electroencephalographic or neuroradiological features which occur specifically in this syndrome. The need to differentiate the findings from those resulting from encephalopathic mechanisms during the gestational and perinatal period is stressed. A distinct typing of seizures and EEG changes is needed in each patient, before definite conclusions about an association of seizures and fra(X) syndrome are drawn. In view of the lack of correlation between IQ and the clinical-neurological measures, a more practical approach to quantifying the mental impairment is proposed.

Limb reduction defects in over one million consecutive livebirths.

Limb reduction defects occurring among 1,213,913 consecutive livebirths in British Columbia during the period 1952-1984 inclusive were reviewed. A total of 659 cases of limb reduction defects were identified, 393 of them involving the long bones and 190 of them more than one limb. The time period 1966-1984, during which ascertainment was consistent, was evaluated, and an incidence of 5.97 per 10,000 livebirths (1 in 1,692 live births) was found. The data were evaluated for trends over time, sex ratio, and regional and ethnic distribution. Associated anomalies of other organ systems in these cases were analyzed, and overall about one-half of the cases have additional defects. The majority of these additional defects affect the musculoskeletal system and include such entities as clubfoot, hip dislocation, and congenital contractures. Defects are also frequent in other organ systems, such as the cardiovascular, gastrointestinal, and genitourinary systems. By far the most common limb defects are terminal longitudinal defects then terminal transverse defects. Of all cases of limb defects, 75% are upper limb and 25% lower limb. We found no evidence that one side is affected more frequently. About 6.5% of cases had another family member registered with a skeletal defect; 12.9% of cases died within the first year of life, the majority (85%) of those dying having additional defects. Etiological considerations are discussed for some subgroups.(ABSTRACT TRUNCATED AT 250 WORDS)

Linkage studies in a large fragile X family.

We have analyzed the segregation of five loci in the region Xq27/28 in a large family affected by the fragile X syndrome. The marker DXS115 (767) is shown to be polymorphic with the enzyme PstI, as well as with BstXI. This marker will be useful in the analysis of both fragile X and haemophilia A families. The data presented here are consistent with the following order of loci: Xcen-F9-DXS105(cX55.7,55E)-DXS98(4D-8)- FRAXA-DXS52(St14)-DXS115(767)-qter.

Spermatogenesis in two patients with the fragile X syndrome. II. First meiosis: light and electron microscopy.

Chromosomes at first meiosis from two males with the fra(X) form of mental retardation were studied using pachytene surface spreads and air-dried preparations. The pachytene sex bivalents showed no discontinuation of the synaptonemal complex in the terminal part of Xq corresponding to band Xq27-28 of the mitotic chromosomes. In both cases the frequency of a secondary association of Xq and Yq appeared to be increased compared with controls. The pairing behavior of autosomal bivalents in pachytene and the frequency and distribution of chiasmata in diakinesis were normal. The impairment of spermatogenesis found in these males may not be caused by a meiotic disorder, but could be related to peritubular or intratubular pressure effects on germ cells.

Brief clinical report: an unusual bandlike web in an infant with lethal multiple pterygium syndrome.

We report on a patient with a lethal multiple pterygium syndrome who also had an unusual, bandlike web across one axilla and partial intestinal atresia. Umbilical cord wrapping with subsequent vascular compromise appears to be the most likely pathogenetic mechanism for the additional anomalies.